Highly fluorinated organic compounds are well known to be chemically and pharmaceutically inert and to be capable of dissolving and transporting large amounts of oxygen. These properties make them potentially useful as oxygen transport agents, "artificial bloods" or red blood cell substitutes and as contrast agents for various imaging modalities, such as nuclear magnetic resonance, ultrasound, and x-ray. However, neat fluorocarbon liquids cannot be injected into the blood stream, because their hydrophobic character makes them immiscible in the blood and as a result, when they are transported into small blood vessels they may cause vascular obstruction and death. As a consequence, for medical uses that require intravascular injection, highly fluorinated organic compounds must be dispersed as physiologically acceptable emulsions. See, e.g., L. C. Clark, Jr. et al., "Emulsions Of Perfluorinated Solvents For Intravascular Gas Transport", Fed. Proc., 34 (6), pp. 1468-77 (1975); K. Yokoyama et al., "A Perfluorochemical Emulsion As An Oxygen Carrier", Artif. Organs (Cleve), 8 (1), pp. 34-40 (1984); and U.S. Pat. Nos. 4,110,474 and 4,187,252.
To date, however, the medical usefulness of such emulsions of highly fluorinated organic compounds as "artificial bloods" or blood substitutes, oxygen transport agents or contrast agents for biological imaging has not been as successful as hoped. This results from the fact that in practice it has not been previously possible to make emulsions that are both stable and incorporate the relatively large amounts of highly fluorinated organic compounds that are required in clinical practice where the total volume of emulsion that can be administered is limited, e.g., as "artificial bloods". Moreover, it has not been previously possible to make such emulsions using highly fluorinated organic compounds that are excreted from the body within a clinically acceptable time period (see U.S. Pat. No. 3,911,138). Finally, even those, admittedly less than therapeutically acceptable, compositions that have been available to date are difficult to sterilize because of their instability at high temperature.
Various attempts have been made to solve these problems and to prepare stable emulsions containing high concentrations of clinically suitable highly fluorinated organic compounds. None has been successful. For example, a variety of fluorocarbons and combinations of them have been used in preparing the emulsions in hopes of improving their stability. None has produced a medically effective and commercially acceptable emulsion that is stable at room temperature. For example, the only fluorocarbon emulsion to reach clinical testing as an "artificial blood", "Fluosol DA 20%" is about a 12% by volume emulsion of two fluorocarbons--perfluorodecalin and perfluorotripropylamine--in a mixture of two surfactants--yolk phospholipid and Pluronic F-68. It is not stable in the liquid state and must be stored frozen (Yokoyama et al., supra). Furthermore, the required presence of the perfluorotripropylamine in this emulsion, to help "stabilize" it, disadvantages the emulsion's medical usefulness because the half-life of the perfluorotripropylamine in the liver and other body tissues is longer than desirable (see, e.g., K. Yokoyama et al., supra). Finally, because this emulsion contains only about 12% fluorocarbon by volume, it is much less therapeutically effective than desired because of its low oxygen content capacity (see, e.g., "Fluosol-DA As A Red Cell Substitute In Acute Anemia", N.E. Jour. Med., 314, pp. 1653-66 (1986).
Emulsions of other perfluorocarbons have likewise not been very effective in avoiding these instability and oxygen capacity problems. For example, an emulsion of perfluoro-4-methyloctahydroquinolidizine (FMOQ) in two surfactants--Pluronic F-68 and yolk phospholipid--must be stored at 4.degree. C. (K. Yokoyama et al., supra).
Various surfactants have also been investigated in the hope that some would produce useful, stable emulsions of highly fluorinated organic compounds for use as oxygen transport agents and "artificial bloods". Again, these attempts have failed. For example, fluorocarbon emulsions containing a hydrogenated phospholipid, a nonionic polymeric surfactant and a surfactant selected from 6-22 C fatty acids, their salts and monoglycerides must also be stored at 4.degree. C. See, e.g., Japanese patent application 59,067,229, U.S. Pat. No. 4,252,827 and Germany Offen. DE 2630506.
Therefore, the medical and non-medical uses of highly fluorinated organic compounds as effective oxygen transport agents, "artificial bloods" or red blood cell substitutes, and contrast agents for biological imaging is still a long sought and important goal.